Highly active anti-retroviral therapy (HAART) has been successful at reducing virus load in the cerebrospinal fluid (CSF) of HIV-1 infected individuals, however a direct relationship between CSF virus load and parenchymal virus load has not been established. Further, the mechanism by which anti-retroviral agents suppress viral load in the central nervous system (CNS) remains unknown, since most antiretroviral agents are unable to cross the blood-brain barrier (BBB), and the kinetics of primate lentiviral turnover in the CNS have not been described. One potentially serious complication of HAART is that poor penetration of antiretroviral agents across the BBB will lead to establishment of a viral reservoir within the CNS parenchyma which could serve to reinfect lymphoid tissues following withdrawal of therapy. The SIV/macaque model has been useful for elucidating many features of lentiviral neuropathogenesis, however, the infrequency of neurovirulence in SIV infected macaques limits the use of this model for assessing the efficacy of therapeutic agents designed to treat or prevent HIV-associated dementia. We have isolated a macrophage tropic strain of SIV (SIVsmmFGb) which is neuropathogenic in over 90 percent of infected pigtailed macaques. In this proposal, we will use the SIVsmmFGb/pigtailed macaque model to investigate three important questions concerning lentiviral neuropathogenesis. First, we will determine the rate of turnover of SIV infected cells in the CNS and compare CSF with parenchymal viral load. We hypothesize that viral decay in the CNS will exhibit slow, second-order kinetics, since macrophages represent the primary productively-infected cells in the CNS. Second, we will directly address the question of whether the CNS functions as a reservoir for virus during treatment with the reverse transcriptase inhibitor PMPA and following discontinuation of PMPA therapy. We hypothesize that maintenance of a reservoir of productively infected cells within the CNS is dependent upon continual recruitment of infected blood monocytes, and that the peripheral lymphoid tissues, not the brain, will be the reservoir of infectious virus. Finally, we will integrate the SIVsmmFGb neuropathogenesis model with an established model for prenatal cocaine exposure in macaques to investigate the effect of prenatal exposure to cocaine on SIV neuropathogenesis. We hypothesize that vascular and immunologic lesions induced by prenatal cocaine exposure will facilitate SIV neuroinvasion in neonatal macaques, leading to increased CNS viral load, and an accelerated progression of neonatal SIV neuropathogenesis.